Abstract

The overall objective of this project is to understand how ethanol acts on brain areas involved in the mediation of reward, and to determine how specific neurotransmitter systems modify the action of ethanol on brain reward pathways. Drugs acting on the serotonergic system reduce voluntary ethanol intake in laboratory animals and in clinical studies. These drugs may act at brain areas involved in reward to reduce alcohol craving. The ventral tegmental areas of Tsai (VTA) is important for mediating the rewarding properties of many drugs of abuse, including ethanol. Whole cell patch recording from acutely dissociated dopaminergic VTA neurons will be used to assess the action of ethanol and serotonin on these cells. Drugs will be applied in known concentrations. Ethanol causes excitation of most VTA neurons in extracellular and intracellular studies. We have shown that serotonin potentiates the excitatory effect of ethanol on VTA neurons, and this effect is mediated by 5-HT/2 receptors. We will investigate changes in specific membrane currents which may underlies serotonin potentiation of ethanol effects.
Specific Aim #1 is to investigate the effects of serotonin and ethanol on potassium currents which mediate the after hyperpolarization following spontaneous action potentials. The specific currents which we intend to examine include two calcium-dependent potassium conductances, SK and BK, A-current (I/A), and the delayed rectifier.
Specific Aim #2 is to determine how M-current, which is reduced by serotonin in other preparations, is affected by ethanol, serotonin and by the combination of ethanol and serotonin, in VT neurons.
Specific Aim #3 is to determine whether serotonin alters h-current (I/h), a hyperpolarization-activated inward rectifier current, and to determine whether the effect of ethanol to enhance I/h is increased in the presence of serotonin. From the results of these experiments, a model will be developed to describe the interactions between the effects of serotonin and ethanol which result in potentiation of ethanol-induced excitation. These studies should elucidate the ionic mechanisms by which serotonin alters the action of ethanol in the VTA. This knowledge could be exploited to develop drugs for the treatment of alcoholism which reduce ethanol craving.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA009125-04A2
Application #
2484189
Study Section
Special Emphasis Panel (ZRG4-ALTX-3 (01))
Project Start
1992-08-01
Project End
2001-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612

  Publications

Dutton 3rd, John W; Chen, Hu; You, Chang et al. (2017) Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area. Addict Biol 22:665-678
Nimitvilai, Sudarat; Herman, Melissa; You, Chang et al. (2014) Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release. Neuropharmacology 82:28-40
Nimitvilai, Sudarat; McElvain, Maureen A; Brodie, Mark S (2013) Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. J Pharmacol Exp Ther 344:253-63
Arora, Devinder S; Nimitvilai, Sudarat; Teppen, Tara L et al. (2013) Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors. Neuropsychopharmacology 38:1674-84
Nimitvilai, S; Arora, D S; McElvain, M A et al. (2012) Reversal of inhibition of putative dopaminergic neurons of the ventral tegmental area: interaction of GABA(B) and D2 receptors. Neuroscience 226:29-39
Nimitvilai, Sudarat; Arora, Devinder S; Brodie, Mark S (2012) Reversal of dopamine inhibition of dopaminergic neurons of the ventral tegmental area is mediated by protein kinase C. Neuropsychopharmacology 37:543-56
Nimitvilai, Sudarat; Brodie, Mark S (2010) Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area. J Pharmacol Exp Ther 333:555-63
Melis, Miriam; Diana, Marco; Enrico, Paolo et al. (2009) Ethanol and acetaldehyde action on central dopamine systems: mechanisms, modulation, and relationship to stress. Alcohol 43:531-9
McDaid, John; McElvain, Maureen A; Brodie, Mark S (2008) Ethanol effects on dopaminergic ventral tegmental area neurons during block of Ih: involvement of barium-sensitive potassium currents. J Neurophysiol 100:1202-10
Koyama, Susumu; Brodie, Mark S; Appel, Sarah B (2007) Ethanol inhibition of m-current and ethanol-induced direct excitation of ventral tegmental area dopamine neurons. J Neurophysiol 97:1977-85

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